Hereditary Breast Cancer (Including BRCA1 and BRCA2)

To compare directly to other hereditary cancer panels offered by ARUP Laboratories, see the Hereditary Cancer Panel Comparison table.

  • Germline analysis of the BRCA1 and BRCA2 genes in individuals with a suspected diagnosis of HBOC syndrome
  • Testing minors for adult-onset conditions is not recommended. Testing will not be performed on minors without prior approval. For additional information, please contact an ARUP genetic counselor at 800-242-2787.
  • Germline analysis of high lifetime risk (>40%) hereditary breast cancer genes (including BRCA1 and BRCA2) for individuals with personal or family history of hereditary breast or other related cancers
  • Testing minors for adult-onset conditions is not recommended. Testing will not be performed on minors without prior approval. For additional information, please contact an ARUP genetic counselor.
  • Germline analysis of moderate and high lifetime risk (>15%) hereditary breast cancer genes (including BRCA1 and BRCA2) for individuals with personal or family history of hereditary breast or other related cancers
  • Testing minors for adult-onset conditions is not recommended. Testing will not be performed on minors without prior approval. For additional information, please contact an ARUP genetic counselor.
  • Testing for a known familial sequence variant by sequencing gene of interest. A copy of the family member’s test result documenting the familial gene variant is REQUIRED.
  • To determine if the variant(s) of interest are detectable by this assay, contact an ARUP genetic counselor.

Pathogenic germline variants in multiple genes have been implicated in hereditary breast cancer. Hereditary cancer syndromes are often characterized by an early age of cancer onset (typically before 50 years of age) and multiple, multifocal, and/or similar cancers in a single individual or in a closely related family member(s). Pathogenic variants in the BRCA1 and BRCA2 genes are associated with the most common cause of hereditary breast cancer, known as BRCA1- and BRCA2-associated hereditary breast and ovarian cancer (HBOC) syndrome. Other inherited causes of hereditary breast cancer have been identified. Additional screening, and in some cases, risk-reducing options have been recommended for individuals with pathogenic variants in moderate to high-risk hereditary breast cancer genes. For a more comprehensive test for hereditary causes of breast and/or gynecological cancers, please see the Hereditary Breast and Gynecological Cancers Panel, which includes an analysis of BRCA1 and BRCA2.

Disease Overview

BRCA1- and BRCA2-Associated HBOC Syndrome

BRCA1- and BRCA2-associated HBOC syndrome is caused by a single germline BRCA1 or BRCA2 pathogenic variant and results in an increased lifetime risk of certain cancers. 

Lifetime Cancer Risk by Type
Cancer Type Cancer Risk by Gene
BRCA1 BRCA2

Breast cancer (female)

55-72% by 70 yrs of age

45-69%

Breast cancer (male)

1-2%

6-8%

Ovarian cancer (including fallopian tube and peritoneal)

39-44%

11-17%

Pancreatic cancer

1-3%

3-5% by 70 yrs of age

Prostate cancer

29% by 85 yrs of age

60% by 85 yrs of age

Melanoma

1.6% (same as general population)

Elevated risk

Source: Petrucelli, 2022 

Others

See Genes Tested table for more information about the other syndromes included in the Hereditary Breast Cancer: High-Risk Panel and Hereditary Breast Cancer: Guidelines-Based Panel.

Genetics

Genes Tested by Panel

Genetic Markers Included in ARUP Breast Cancer Panel Tests
Gene BRCA1 and BRCA2-Associated HBOC Syndrome Panel, Sequencing and Deletion/Duplication 3001855 Hereditary Breast Cancer High-Risk Panel, Sequencing and Deletion/Duplication 3005632 Hereditary Breast Cancer Guidelines-Based Panel, Sequencing and Deletion/Duplication 3005654

BRCA1

BRCA2

CDH1

 

PALB2

 

PTEN

 

TP53

 

ATM

 

 

BARD1

 

 

CDH1

 

 

CHEK2

 

 

NF1

 

 

STK11

 

 

See Genes Tested table for more information regarding the genes included in all three panels.

Etiology

At least 5-10% of all breast cancers are associated with a hereditary cause.  

Prevalence

BRCA1 and BRCA2 genes

  • One in 400 individuals from the general population or 1 in 40 Ashkenazi Jewish individuals have a BRCA1 or BRCA2 pathogenic variant.  

Inheritance

  • Autosomal dominant for all genes on the three described panels
  • Additionally, some genes are associated with autosomal recessive childhood cancer predisposition or other syndromes.

BRCA1 and BRCA2 Pathogenic Founder Variants

  • The following three founder variants are estimated to make up 99% of pathogenic variants in individuals of Ashkenazi Jewish descent :
    • BRCA1 c.68_69delAG (also known as 185delAG)
    • BRCA1 c.5266dupC (also known as 5382insC)
    • BRCA2 c.5946delT (also known as 6174delT)
  • Additional founder variants have been identified in other populations, including African, Amish, Ammassalik (Greenlandic), and Icelandic populations. 

Test Interpretation

Contraindications for Ordering

  • These tests should not be ordered to detect somatic variants associated with malignancy because sensitivity for mosaic variants is low with the methodology used for germline assays.
  • Individuals with hematologic malignancy and/or a previous allogeneic bone marrow transplantation should not undergo molecular genetic testing on a peripheral blood specimen.
    • Testing of cultured fibroblasts is required for accurate interpretation of test results.
  • When a relative has a previously identified pathogenic variant, see Familial Targeted Sequencing (3005867).

Methodology

This test is performed using the following sequence of steps:

  • Selected genomic regions, primarily coding exons and exon-intron boundaries, from the targeted genes are isolated from extracted genomic DNA using a probe-based hybrid capture enrichment workflow.
  • Enriched DNA is sequenced by massively parallel sequencing (MPS; also known as next generation sequencing [NGS]) followed by paired-end read alignment and variant calling using a custom bioinformatics pipeline. The pipeline includes an algorithm for the detection of large (single exon-level or larger) deletions and duplications.
  • Sanger sequencing is performed as necessary to fill in regions of low coverage and in certain situations, to confirm variant calls.
  • Large deletion/duplication calls made using MPS are confirmed by an orthogonal exon-level microarray when sample quality and technical conditions allow.
  • Bidirectional Sanger sequencing is performed on the following gene and exon:
    • PTEN (NM_000314) 9

Clinical Sensitivity

BRCA1 and em>BRCA2-Associated HBOC Syndrome Panel, Sequencing and Deletion/Duplication

  • Greater than 98% for BRCA1- and BRCA2-associated hereditary breast and ovarian cancer syndrome 
    • BRCA1 variants
      • Approximately 87-89% are detectable by sequencing
      • Approximately 11-13% detectable by deletion/duplication analysis
    • BRCA2 variants
      • Approximately 97-98% are detectable by sequencing
      • Approximately 2-3% are detectable by deletion/duplication analysis

Hereditary Breast Cancer High-Risk Panel, Sequencing and Deletion/Duplication and Hereditary Breast Cancer Guidelines-Based Panel, Sequencing and Deletion/Duplication

  • BRCA1 and BRCA2 sequencing and deletion/duplication testing detects approximately 20-60% of hereditary breast and/or ovarian cancers, in general.  
  • Clinical sensitivity of additional genes is largely unknown.

Analytic Sensitivity

Variant Class Analytic Sensitivity (PPA) Estimatea (%)
and 95% Credibility Region (%)
Analytic Specificity (NPA) (%)

SNVs

>99 (96.9-99.4)

>99.9

Deletions 1-10 bpb

93.8 (84.3-98.2)

>99.9

Insertions 1-10 bpb

94.8 (86.8-98.5)

>99.9

Exon-levelc deletions

97.8% (90.3-99.8%) [2 exons or larger]

62.5% (38.3-82.6%) [single exon]

>99.9

Exon-levelc duplications

83.3% (56.4-96.4%) [3 exons or larger]

>99.9

aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived. These values do not apply to testing performed by multiplex ligation-dependent probe amplification (MLPA).

bVariants greater than 10 bp may be detected, but the analytical sensitivity may be reduced.

cIn most cases, a single exon deletion or duplication is less than 450 bp and 3 exons span a genomic region larger than 700 bp.

bp, base pairs; NPA, negative percent agreement; PPA, positive percent agreement; SNVs, single nucleotide variants

Limitations

  • A negative result does not exclude a heritable form of cancer.
  • Diagnostic errors can occur due to rare sequence variations.
  • Interpretation of this test result may be impacted if this individual has had an allogeneic stem cell transplantation.
  • The following will not be evaluated:
    • Variants outside the coding regions and intron-exon boundaries of the targeted genes
    • Regulatory region variants and deep intronic variants
    • Breakpoints of large deletions/duplications
    • The following exons are not sequenced due to technical limitations of the assay:
      • BRCA1 (NM_007300) 13
      • CHEK2 (NM_001005735) 3; (NM_001349956) 4
  • The following may not be detected:
    • Deletions/duplications/insertions of any size by massively parallel sequencing
    • Large duplications less than 3 exons in size
    • Deletions/duplications in the following exons:
      • BRCA1 (NM_007294, NM_007299, NM_007300) 2; (NM_007298) 1
      • CDH1 (NM_001317185) 10
      • CHEK2 (NM_007194) 11-15; (NM_001005735) 3,12-16; (NM_001257387) 12-16; (NM_001349956) 4,10-14; (NM_145862) 10-14;
      • PTEN (NM_000314, NM_001304718) 9; (NM_001304717) 1,10
    • Noncoding transcripts
    • Some variants due to technical limitations in the presence of pseudogenes and/or repetitive or homologous regions
    • Low-level somatic variants

Genes Tested

The following genes are included on one or more of the panels described in this document. For a list of genes tested by each panel, see the Genes Tested by Panel section.

To compare directly to other hereditary cancer panels offered by ARUP Laboratories, see the Hereditary Cancer Panel Comparison table.

Gene MIM Number Disorder Inheritance

ATM

607585

Breast, colorectal,a ovarian, pancreas, prostate

AD

Ataxia-telangiectasia

AR

BARD1

601593

Breast

AD

BRCA1

113705

HBOC syndrome

Associated cancer(s)/tumor(s): breast, ovarian, fallopian tube, peritoneal, pancreatic, prostate

AD

Fanconi anemia, complementation group S

AR

BRCA2

600185

HBOC syndrome

Associated cancer(s)/tumor(s): breast, ovarian, fallopian tube, peritoneal, pancreatic, prostate, melanoma

AD

Fanconi anemia, complementation group D1

AR

CDH1

192090

HDGC

Diffuse gastric, lobular breast

AD

CHEK2

604373

Breast, colorectal, prostate, thyroida

AD

NF1

613113

NF1

Breast, GIST, gliomas, leukemia, malignant peripheral nerve sheath tumors, neurofibromas, pheochromocytoma

AD

PALB2

610355

Breast, ovarian, pancreas, prostate

AD

Fanconi anemia, complementation group N

AR

PTEN

601728

Cowden syndrome/PTEN hamartoma tumor syndrome

Breast, colorectal, endometrial, Lhermitte-Duclos disease (cerebellar dysplastic gangliocytoma), melanoma,a renal cell carcinoma, thyroid, and others

AD

STK11

602216

PJS

Breast, cervix, colorectal, endometrial, lung, ovarian (sex cord with annular tubules), pancreas, Peutz-Jeghers-type hamartomatous polyps, small intestine, stomach, testes

AD

TP53

191170

LFS

Adrenocortical carcinoma, breast, choroid plexus carcinoma, CNS, colorectal, melanoma,a osteosarcoma, pancreas, prostate, renal, rhabdomyosarcoma, soft tissue sarcoma, stomach, thyroid, and others

AD

aAssociation is suggested but not well-established at this time.

AD, autosomal dominant; AR, autosomal recessive; CNS, central nervous system; HDGC, hereditary diffuse gastric cancer; LFS, Li-Fraumeni syndrome; NF1, neurofibromatosis type 1; PJS, Peutz-Jeghers syndrome

References